Cocaine abuse is a significant public health problem, with approximately 1.4 million Americans meeting the DSMIV criteria for cocaine dependence and acute overdoses causing nearly 500,000 emergency room visits each year. In spite of this, there are remarkably few effective treatments for cocaine addiction and abuse. Part of the difficulty in the medical treatment of cocaine addiction is that even after successful short-term treatment, environmental cues can evoke craving and drug relapse. Behavioral and neurobiological approaches to memory have identified extinction, in which the relation between the cue and the drug is severed, as a way to eliminate conditioned behavior. A challenge for extinction-based therapies, however, is that extinguished behavior often returns with time or after re-exposure to the drug. In our initial period of support, we examined pharmacological approaches that, when paired with behavioral extinction, generated a rapid and persistent loss of drug-seeking that was resistant to reinstatement challenges (relapse-like behavior). Our focus has been on the regulation of gene expression necessary for long-term memory formation, which involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification is a main mechanism of epigenetic gene regulation, which is emerging as a major molecular pathway involved in synaptic plasticity and memory storage. Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level. Importantly, in animal models of addiction, chronic drug exposure induces stable chromatin modification resulting in stable synaptic plasticity changes, which is thought to drive persistnt changes in behavior. Considering the substantial overlap in the circuitry involved in drug addiction and learning and memory pathways, the focus of this grant proposal is to modulate learning and memory pathways in order to extinguish drug associated memories. In this renewal application, we focus on a specific mechanism of regulating histone acetylation via histone deacetylase 3 (HDAC3). We use genetic, viral, and pharmacological manipulations to investigate the role of HDAC3 in extinction of cocaine-induced conditioned place preferences and intravenous cocaine self-administration. We hypothesize that HDAC3 is a key negative regulator of extinction of drug-seeking behavior and that HDAC3 modulates extinction via regulation of Nr4a (nuclear orphan receptor) gene family. In Specific Aim 1, we will use a novel pharmacological approach to determine the role of HDAC3 specifically in memory consolidation during extinction. In Specific Aim 2, we will use a genetic and viral approach to determine the role of long-term modulation of HDAC3 in extinction. In Specific Aim 3, we will use a molecular approach to determine the role of the Nr4a gene family (HDAC3 target genes) in extinction. Our approach promises to elucidate behavioral, systems, and epigenetic mechanisms of extinction and elucidate novel molecular targets for pharmacological interventions.